Residual ridge (RR) refers to the clinical alveolar ridge that remains after the bone and soft tissues have healed following tooth extraction. This ridge undergoes resorption, which is most rapid during the first six months of post-extraction. Subsequently, bone resorption continues at a slower pace throughout life, leading to significant loss of jaw structure over time. This process is commonly known as residual ridge resorption (RRR). RRR is a major factor contributing to the loss of stability and retention, especially in mandibular complete dentures. Severe resorption of the maxillary and mandibular ridges can also lead to a sunken cheek appearance, poorly fitting and unstable dentures, and associated pain and discomfort. Though the etiology of residual ridge resorption remains unclear. It is believed that certain cytokines and individual genetic variations may influence the RRR process. Thus, reviewing the studies that discuss genetic association with the health and resorption of alveolar bone may give clear view on the etiology, help to define the risk and strategize preventive and personalized management of the disease. Hence, we undertook a scoping review to understand the potential genetic factors influencing the Residual ridge resorption (RRR). This review employed PRISMA-ScR extension protocols for scoping review. The results of the study provided significant association between genetic polymorphisms, especially of single gene nucleotide polymorphisms with mandibular residual ridge resorption. Hence understanding the genetic predisposition of patients can guide the clinicians in identifying patients at higher risk of RRR, enabling preventive measures, proactive intervention and careful designing of the prothesis.

Chitinase 3-like 1 (CHI3L1) has been implicated in the pathogenesis of various diseases, including cancer. In our previous study, we found that anti-CHIL1 antibody inhibited lung tumorigenesis. It has been reported that CHI3L1 is highly overexpressed in colon cancer tissue compared with normal tissue, and high levels of serum CHI3L1 have been associated with worse colon cancer prognosis. We investigated the anticancer effect of an anti-CHI3L1 antibody on colon cancer cells. The anti-CHI3L1 antibody inhibited the cell growth of colon cancer cells in a concentration-dependent manner. The anti-CHI3L1 antibody also reduced the migration but increased apoptotic cell death in colon cancer cells. Using STRING (Search Tool for the Retrieval of Interacting Genes/Proteins), we identified an association between VEGFA and CHI3L1 in colon cancer. We confirmed interaction between VEGFA and CHI3L1 through immunoprecipitation. Furthermore, the combination treatment of the anti-CHI3L1 antibody and VEGFA siRNA inhibited cell growth but increased apoptotic cell death. Additionally, using the Human Base database, we found that CHI3L1 and VEGFA are associated with nicotinamide phosphoribosyltransferase (NAMPT). Furthermore, combining the anti-CHI3L1 antibody and NAMPT siRNA more effectively reduced cell growth and the expression of CHI3L1, VEGFA, and cell growth-related proteins, but significantly increased apoptosis-related proteins. The combination of VEGFA siRNA and NAMPT siRNA more effectively inhibited cell growth. Anti-CHI3L1 antibody inhibited the production of ATP and NADH in colon cancer and had a higher inhibitory effect on these levels when combined with NAMPT siRNA These data demonstrated that anti-CHI3L1 antibody is useful as a potential therapy for colon cancer by inhibiting NAMPT-dependent VEGFA expression and ATP and NADH levels.

Vascular dementia (VaD) significantly impairs patients' quality of life and imposes a major social and economic burden. Electroacupuncture (EA), a contemporary modification of traditional acupuncture, has demonstrated potential in improving cognitive function in VaD, particularly when applied at the Shenting and Baihui. However, the underlying mechanisms remain inadequately understood. Elucidating how EA ameliorates cognitive deficits is critical for validating its clinical application and advancing non-pharmacological interventions for neurodegenerative disorders. This study aimed to investigate the neuroprotective mechanisms of electroacupuncture at these acupoints on cognitive function in VaD rats. VaD was induced in male Sprague-Dawley rats through bilateral common carotid artery occlusion (BCAO), with sham rats serving as controls. Rats were subsequently divided into three groups: BCAO, BCAO + EA and BCAO + EA + YC-1 (a HIF-1α inhibitor). Electroacupuncture was applied to the Shenting and Baihui. Cerebral blood flow (CBF) was measured using dynamic susceptibility contrast functional MRI, and cognitive recovery was evaluated through the Morris water maze. Immunohistochemical analysis quantified myelin repair and angiogenesis, while expression of HIF-1α, VEGF and VEGFR2 in white matter was quantified using PCR and Western blot. The results indicated that electroacupuncture improved learning and memory, increased CBF, enhanced myelin recovery and promoted angiogenesis in VaD rats. The expression of HIF-1α, VEGF and VEGFR2 in the white matter was significantly elevated in VaD rats. Electroacupuncture at Shenting and Baihui activates the HIF-1α/VEGF/VEGFR2 pathway, enhances angiogenesis, white matter perfusion and myelin repair, thereby restoring cognitive function in VaD rats.

Traditional Chinese Medicine (TCM) shows growing potential as an adjunct or alternative therapy for vascular occlusion diseases (e.g., stroke, peripheral artery disease) by promoting therapeutic angiogenesis to restore blood flow in ischemic regions while minimizing side effects.

This review examines TCM-mediated angiogenesis mechanisms and therapeutic advances in vascular occlusion management, establishing a theoretical foundation for clinical translation and precision medicine development.

We systematically analyzed PubMed articles on TCM-induced angiogenesis in vascular occlusion diseases, focusing on herbal formulations, single herbs, bioactive compounds, and their associated signaling pathways. Search PubMed for studies investigating the role of Chinese herbal medicine (TCM), natural compounds, and herbal medicine in angiogenesis, while excluding research related to cancer, tumor, or oncological contexts.

TCM formulas, individual herbs, and monomeric compounds enhance endothelial cell proliferation, migration, and tube formation via pathways such as HIF/VEGF, PI3K/AKT, NOTCH, BMP/ALK, and Apelin/APJ, improving ischemic blood flow.

This review highlights angiogenesis as a novel strategy for vascular occlusive diseases and underscores TCM's efficacy through multi-target angiogenic regulation mechanism.However, further research using modern medical technologies is needed to optimize clinical application and advance precision medicine.

Intensive inflammation induced via bacterial infection seriously disturbs the immune-microenvironment and compromise the neovascularization in the skin wound. On the basis of reducing bacterial infections, alleviating inflammatory response and rebuild the crosstalk between macrophages and vascular endothelial cell (VEC) serve as the key strategy for facilitating infected wound healing. Herein, manganese tetroxide (Mn3O4) nanozymes and polydopamine-coated hydroxyapatite (PHA) nanoparticles were loaded on the gelatin methacryloyl (GelMA) hydrogel, which was subsequently crosslinked by the UV light to construct a multifunctional hydrogel wound dressing GelMA-PHA-Mn3O4 with excellent anti-bacterial, immuno-regulation and angiogenic properties. Triggered by near infrared (NIR), PHA exhibited photothermal effect and effectively eradicated Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) biofilm. On the other hand, Mn3O4 nanozymes in hydrogel exhibit desirable reactive oxygen species (ROS) scavenging capacity due to the redox cycle between Mn2+ and Mn3+, which successfully transform the LPS-induced macrophage phenotype from pro-inflammation M1 to anti-inflammation M2. Notably, the interaction between macrophages and VECs was subsequently reconstructed and exhibited an evident pro-angiogenic phenomenon along with the improvement of local immuno-microenvironment. In vivo study further verified that the GelMA-PHA-Mn3O4 hydrogel combined with NIR irradiation could accelerate the healing of infected wound through the prominent anti-bacterial and immuno-regulation effect. The collagen deposition and formation of blood vessel in the wound were active. Above, this study demonstrated that the GelMA-PHA-Mn3O4 hydrogel represents a promising approach for managing infected wounds, with an anticipated prospect in clinical application.

The tumor microenvironment (TME) plays a pivotal role in cancer progression and metastasis, with vascular endothelial growth factor (VEGF) signaling serving as a key regulator of tumor angiogenesis and immune evasion. VEGF induces abnormal blood vessel formation, promoting tumor growth, immune suppression, and metastasis through epithelialmesenchymal transition (EMT). As a result, VEGF signaling has become a critical therapeutic target in cancer treatment. This review examines the molecular mechanisms driving VEGF-mediated tumor growth and angiogenesis, with a focus on the interaction between tumor and endothelial cells and the dual role of VEGF in fostering vascularization and immune suppression. Current anti-VEGF therapies, including monoclonal antibodies (e.g., bevacizumab) and tyrosine kinase inhibitors (TKIs), have demonstrated efficacy and have received FDA approval for various cancers; however, therapeutic resistance remains a significant challenge. Strategies to overcome resistance, such as novel VEGF inhibitors, vascular normalization approaches, and combination therapies with immune checkpoint inhibitors, have been explored. Additionally, future directions emphasize the need for personalized approaches to improve treatment efficacy and reduce metastasis. A comprehensive understanding of VEGF signaling in the TME may pave the way for more effective cancer therapies.

Tumour angiogenesis is the formation of new blood vessels to support the growth of a tumour. This process is critical for tumour progression and metastasis, making it an attractive approach to cancer therapy. Natural products derived from plants, animals or microorganisms exert anti-angiogenic properties and can be used to inhibit tumour growth and progression. In this review, we comprehensively report on the current status of natural products against tumour angiogenesis from four perspectives until March 2023: (1) the role of pro-angiogenic factors and antiangiogenic factors in tumour angiogenesis; (2) the development of anti-tumour angiogenesis therapy (monoclonal antibodies, VEGFR-targeted small molecules and fusion proteins); (3) the summary of anti-angiogenic natural agents, including polyphenols, polysaccharides, alkaloids, terpenoids, saponins and their mechanisms of action, and (4) the future perspectives of anti-angiogenic natural products (bioavailability improvement, testing of dosage and side effects, combination use and discovery of unique natural-based compounds). Our review aims to better understand the potential of natural products for drug development in inhibiting tumour angiogenesis and further aid the effective transition of these outcomes into clinical trials. LINKED ARTICLES: This article is part of a themed issue Natural Products and Cancer: From Drug Discovery to Prevention and Therapy. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.10/issuetoc.

Anti-PD-L1 antibodies are associated with responses in <25% of patients with metastatic human papillomavirus-associated malignancies. VEGF signaling causes immune evasion and immune suppression within the tumor. We evaluated the anti-PD-L1 antibody atezolizumab and anti-VEGF antibody bevacizumab for patients with unresectable, advanced anal cancer.

For this phase II study, participants with previously treated, immunotherapy-naïve anal cancer received atezolizumab (1,200 mg) and bevacizumab (15 mg/kg) intravenously every 21 days. Responses were evaluated every 9 weeks (RECIST version 1.1). The primary endpoint was the best radiographic response. Median survival was estimated by Kaplan-Meier and compared for selected biomarkers (including paired pre- and on-treatment biopsies) using a log-rank test.

Among 20 participants, the overall response rate was 11% [95% confidence interval (CI): 1.2-32]. Median progression-free survival and overall survival were 4.1 months (95% CI, 2.6-not assessable) and 11.6 months (95% CI, 9.5-20), respectively. One grade 5 bevacizumab-related bowel perforation occurred. Analyses of 16 paired biopsies linked increases in IFN-γ (P = 0.03) and inflammatory response (P = 0.02) gene expression signatures with prolonged progression-free survival, as did increases in CD3+CD8+PD1+ (P = 0.02) cells and decreases in CD3+FoxP3+ cells (P = 0.04) from 10 paired biopsies with multiplex immunofluorescence. A subgroup of anal cancers characterized by the SBS31 "prior-platinum" signature demonstrated shorter median overall survival (HR, 6.3; 95% CI, 1.2-32; P = 0.01).

Atezolizumab and bevacizumab demonstrate activity similar to anti-PD-1 antibodies alone for unresectable anal cancer. Our translational data identify undescribed chromosomal and transcriptomic biomarkers associated with survival for metastatic anal cancer. These correlative findings warrant confirmation and further validation in larger, prospective immunotherapy trials for advanced anal cancer.

The objective of this article is to summarize the research progress and discuss the current difficulties of gene-based therapeutic angiogenesis in lower limb ischemic diseases, so as to provide new research directions for the non-invasive treatment of lower limb ischemia. The basic and clinical trials of gene-based therapeutic angiogenesis in lower limb ischemia in recent years were read and reviewed. Growth factors such as vascular endothelial growth factor, hepatocyte growth factor, and fibroblast growth factor have been extensively studied for their application in lower limb ischemic diseases. However, clinical studies across various phases have shown inconsistent efficacy endpoints. The efficacy of gene therapy remains questionable. Before exploring efficient methods of delivering pro-angiogenic genes to ischemic tissues, clarification is needed regarding whether the goal of gene therapy is to simply promote collateral circulation or create a conducive tissue microenvironment for angiogenesis. In conclusion, pre-clinical and clinical studies have demonstrated the potential of therapeutic angiogenesis, but more systematic and comprehensive research is needed to explore safer, more effective, and cost-effective treatment methods.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that typically lacks effective targeted therapies, leading to limited treatment options. Chemotherapy remains the primary treatment modality; however, in recent years, new immunotherapy approaches, such as immune checkpoint inhibitors, have shown positive results in some patients. Although the development of TNBC is closely associated with BRCA gene mutations, the tumor immune microenvironment (TIME) plays a crucial role in tumor progression and immune escape. Tumor angiogenesis, the accumulation of immunosuppressive cells, and alterations in immune molecules collectively shape an environment unfavorable for anti-tumor immune responses. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) promote immune escape by secreting immunosuppressive factors. Therefore, combination strategies of anti-angiogenic and immune checkpoint inhibitory therapies have shown synergistic effects in clinical trials, while new targeted therapies such as TGF-β inhibitors and IL-1β inhibitors offer new options for TNBC treatment. With the development of personalized medicine, combining immunotherapy and targeted therapies brings new hope for TNBC patients.

Vascular endothelial growth factors (VEGFs) play a crucial role in regulating physiological angiogenesis and homeostasis during growth and development. Recent advancements in our knowledge of VEGFs have revealed their complex role in coordinating vascular homeostasis and pathological role in various airway allergic reactions and structural remodeling, especially in allergic asthma and allergic rhinitis (AR), which has become more apparent.

After an extensive search of PubMed and Web of Science databases, our review covered articles published from 1989 to 2024. The purpose of this review was to review previous studies on VEGFs involved in inflammatory progression and tissue remodeling in airway allergic diseases, to summarize the relevant pathways. This article further reviews that VEGFs and their receptors can also be potential targets for treating airway allergic diseases.

The prevalence of airway allergic diseases is increasing, which has caused a serious economic burden. VEGFs and their receptors have been recognized as potential targets for therapeutic interventions, which have been effectively applied in the treatment of tumors and other diseases. Fully elucidating the involvement of VEGFs in the disease process will help us understand their mechanisms of action and develop targeted therapies for allergic diseases.

The presence of circulating cytokines has a significant impact on the development and progression of vestibular disorders. However, further investigation is needed to determine the direction of causation and causal effects. By applying two-sample Mendelian randomization (MR), we analyzed the potential causal connection between 41 circulating cytokines and vestibular disorders using the integrated data from genome-wide association studies (GWAS). The major analysis utilized for MR was inverse variance weighted (IVW). To examine reverse causation, we conducted reverse MR analysis. In addition, we assessed the robustness of the findings by performing pleiotropy and heterogeneity tests. Our results demonstrated that two circulating cytokines were significantly correlated with vestibular disorders risk. More specifically, vascular endothelial growth factor [IVW, odds ratio (OR) = 0.999, 95% confidence interval (CI) = 0.999-1.000, P = 0.046] and interleukin-7 (IVW, OR = 0.999, 95% CI = 0.998-1.000, P = 0.033) were negatively correlated with vestibular disorders risks, respectively. No evidence was identified to support associations between the remaining 39 circulating cytokines and vestibular disorders. These findings reveal a distinct correlation between circulating cytokines and vestibular diseases, providing a novel perspective and potential biological target for future clinical interventions for vestibular disorders.

Mesenchymal stem cell (MSC)-based therapy may be a future treatment for myocardial infarction (MI). However, few studies have assessed the therapeutic efficacy of adipose tissue-derived MSCs (ADSCs) obtained from elderly patients in comparison to that of bone marrow-derived MSCs (BMSCs) from the same elderly patients. The metabolomics results revealed a significantly higher L-arginine excretion from aged ADSCs vs BMSCs in hypoxic conditions. This was hypothesized as the possible mechanism that ADSCs showed an improved angiogenic capacity and enhanced the therapeutic effect on ischemic heart diseases.

To investigate the role of L-arginine in enhancing angiogenesis and cardiac protection by comparing ADSCs and BMSCs in hypoxic conditions for MI therapy.

Metabolomic profiling of supernatants from ADSCs and BMSCs under hypoxic conditions were performed. Then, arginine succinate lyase (ASL) overexpression and short hairpin RNA plasmid were prepared and transfected into BMSCs. Subsequently, in vitro wound healing and Matrigel tube formation assays were used to verify the proangiogenetic effects of ADSC positive control, BMSCs, BMSCs ASL short hairpin RNA, BMSCs ASL overexpressed, and BMSC negative control on cocultured human umbilical vein endothelial cells. All sample sizes, which were determined to meet the statistical requirements and be greater than 3, were established on the basis of previously established literature standards. The protein levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor, etc. were detected. In vivo, the five types of cells were transplanted into the infarcted area of MI rat models, and the therapeutic effects of the transplanted cells were evaluated by echocardiography on cardiac function and by Masson's staining/terminal-deoxynucleotidyl transferase mediated nick end labeling assay/immunofluorescence detection on the infarcted area.

Metabolomic analysis showed that L-arginine was increased. Using ASL gene transfection, we upregulated the production of L-arginine in aged patient-derived BMSCs in vitro, which in turn enhanced mitogen activated protein kinase and VEGF receptor 2 protein expression, VEGF and basic fibroblast growth factor secretion, and inductive angiogenesis to levels comparable to donor-matched ADSCs. After the cell transplantation in vivo, the modified BMSCs as well as ADSCs exhibited decreased apoptotic cells, enhanced vessel formation, reduced scar size, and improved cardiac function in the MI rat model. The therapeutic efficacy decreased by inhibiting L-arginine synthesis.

L-arginine is important for inducing therapeutic angiogenesis for ADSCs and BMSCs in hypoxic conditions. ADSCs have higher L-arginine secretion, which leads to better angiogenesis induction and cardiac protection. ADSC transplantation is a promising autologous cell therapy strategy in the context of the present aging society.

Renal cell carcinoma (RCC) is characterized by a high degree of genomic but also functional intratumoral heterogeneity (ITH). Mutations in VHL, chromatin remodeling genes such as SETD2 and genes that regulate the PI3K/AKT/mTOR pathway have been identified as recurrent drivers despite genomic ITH. Whether and to what extent these mutations shape functional ITH including the formation of spatial niches is incompletely understood. Herein, we analyze the correlation between mutational drivers and their functional proxies in a spatially defined manner.

A total of 23 RCCs were analyzed by panel next-generation sequencing followed by immunohistochemistry for five functional proxies for key genetic alterations including the expression of CD31, GLUT1, phospho-mTOR S2448, H3K36me3 and Ki-67. Antibody stainings were scored semiquantitatively in the tumor periphery and the tumor center.

Unexpectedly, the presence of a VHL mutation was not found to correlate with its functional proxies including the expression of CD31/microvessel density or the expression of the glucose transporter GLUT1. Likewise, there was no correlation between the presence of activating mutations in genes of the PI3K/AKT/mTOR pathway and the expression of activated phospho-mTOR S2448. Furthermore, mutations in the methyltransferase gene SETD2 were not found to correlate with the expression level of its downstream target H3K36me3. Lastly, there was no correlation between the expression of the proliferation marker Ki-67 and the number of driver mutations.

This proof-of-concept study adds genotype-phenotype heterogeneity as additional layer of complexity to the known genomic and functional ITH in RCC.

A developing tumor relies heavily on blood vessels to supply oxygen and nutrients. As a result, angiogenesis, the formation of new blood vessels, supports tumor growth and progression. Similarly, lymphangiogenesis, the formation of new lymphatic vessels, plays a critical role in metastatic dissemination by providing pathways for malignant cells to spread. The tumor microenvironment is crucial for establishing and maintaining these vascular networks, with innate immune cells playing a key regulatory role. Notably, immune cells are specifically enriched in barrier tissues, such as the skin, emphasizing their importance in skin malignancies. Therefore, understanding their role in regulating angiogenesis and lymphangiogenesis is essential for developing novel therapeutic strategies. This review article explores how innate immune cells influence tumor vasculature and highlights the therapeutic potential that may arise from this knowledge.

The objective of this study was to assess the relationship of VEGF-C and LVD with pathoclinical factors of potential prognostic value and with the survival time of gastric cancer patients.

A total of 103 radically operated patients for gastric cancer who did not undergo neoadjuvant therapy were included in this study. The minimum follow-up period after surgery was 61 months. VEGF-C and lymphatic vessels were immunohistochemically determined using antibodies, including VEGF-C (c-20) sc 1881-Goat Polyclonal IgG (Santa Cruz Biotechnology) and Podoplanin D2-40 Mouse Monoclonal Antibody (ROCHE). The relationship between VEGF-C expression in gastric adenocarcinoma cells and the density of lymphatic vessels at the periphery of the primary tumor was assessed, along with the relationships of VEGF-C and LVD with selected pathoclinical parameters of gastric cancer and prognosis.

VEGF-C overexpression was associated with increased LVD (Mann-Whitney U test, p = 0.03) and the Lauren intestinal type of cancer (Pearson's chi-square test, p < 0.001). Increased LVD was more often associated with cancers located beyond the cardia (Mann-Whitney U test, p = 0.04). We did not demonstrate an association of VEGF-C or LVD with OS or with prognostic features, such as pT, pN, or pTNM staging. However, in the Lauren intestinal type of cancer, VEGF-C overexpression correlated with shorter OS (log-rank, p = 0.01) and, at the level of p = 0.05 in multivariate analysis, it had an independent negative prognostic value.

Peritumoral overexpression of VEGF-C in primary gastric cancer tumors is associated with increased LVD. The Lauren intestinal type of cancer is associated with VEGF-C overexpression. The overexpression of VEGF-C in intestinal-type gastric cancer is associated with worse prognosis.

Angiogenesis is a crucial and challenging requirement for the regeneration and repair of damaged tissues, particularly for critical-sized ones. To address this challenge, in this study, we fabricated a cell-communicating gelatin methacryloyl (GelMA) hydrogel using core-shell silica nanoparticles conjugated with roxadustat (FG-4592) and a VEGF-mimetic aptamer (Apt02). This hydrogel promotes tube formation and prevascularization synergistically through both extracellular and intracellular pathways in human umbilical vein endothelial cells (HUVEC), with FG-4592 acting via the extracellular pathway and Apt02 via the intracellular pathway. Fluorophore carbon quantum dot was synthesized and used as a core for constructing core-shell amine-functionalized silica nanoparticles (CQD@MSN-NH2). Using human serum albumin (HSA) as a protein linker, FG-4592 was conjugated on the surface of the nanoparticles to the finalized CQD@MSN@HSA@FG-4592 (CMHF) theranostic proangiogenic nanoparticle. Several techniques were used to characterize structural and cytotoxic properties of CMHF nanoparticles. On the other hand, Apt02 was incorporated into the GelMA hydrogel to induce angiogenesis extracellularly. Results showed that the CMHF nanoparticle and Apt02 are cyto-compatible in periodontal ligament fibroblasts (PDLF) and HUVEC. The HUVEC tube formation assay indicated that 1.0 μM Apt02, 20 μM FG-4592, and 35 μg/mL of CMHF individually induced angiogenesis in HUVEC when 10 ng/mL VEGF was used as a positive control. Western blot and quantitative polymerase chain reaction assays of four genes revealed Apt02 to have an extracellular mechanism of action while FG-4592 increases cellular concentration of the hypoxia-inducible factor-1α (Hif-1α) transcription factor intercellularly and recruits HUVEC to form tube-like vessels both in vitro and ex ovo. In summary, our study introduces an injectable hydrogel containing a blend of 5% GelMA, 1.0 μM Apt02, and 35 μg/mL CMHF nanoparticles, which effectively enhances angiogenesis by activating both extracellular (through VEGFR) and intracellular (by Hif-1α overexpression) pathways and is more effective when targeting only one pathway.

PD-L1, an immune checkpoint inhibitor, and VEGFR2, essential for cancer metastasis, play pivotal roles in tumorigenesis. However, their miniature bispecific intracellular nanobodies for combining check-point blockade and anti-metastasis anticancer therapy remain underexplored.

The intrabodies were developed using gene cloning technology. Specificity of the intrabodies was testified using Western blot, co-immunoprecipitation (co-IP) analysis, antibody competitive binding assay, flow cytometry analysis, etc. Checkpoint blockade was demonstrated using antibody-antigen competitive binding assay. Cancer cell migration was determined using scratch assay. Combined anti-cancer therapeutic efficacy of FAP1V2 was determined in vivo of mice models. The PD-1hi immune cells, TCR βhi and CD25hi T-cells were analyzed by flow cytometry, and cancer cell metastasis was performed using immune-fluorescence analysis on lung and liver tissues. Transcriptome analysis was performed to explore signaling pathways associated with the enhanced anticancer efficiency.

Bispecific intrabody FAP1V2 fused with antibody VH regions, was successfully developed and verified with its ability to target and block human and mouse PD-L1 and VEGFR2, inhibiting cancer cell binding to PD-1 and reducing their migratory capacity. Compared to the other treatment, two-rounds of transient FAP1V2 expression in LLC cells in experimental mice models achieved remarkable tumor inhibition, which brought about complete immune inhibition on growth of secondary-round of LLC tumor in 1/6 of the tested mice, inspired long-term activation of TCR βhi T cells and increased their infiltration to tumors, inhibited the emergence of PD-1hi immune cells, indicating prevented T cell depletion. The elevated CD25 expression also supported the success in enhancing immune response reported by elevated T cell activity in spleen. Transcriptome analysis identified critical intracellular pathways regulated by the concurrent blockade of PD-L1 and VEGFR2.

PD-L1 and VEGFR2- bispecific VH intracellular nanobody was highly biocompatible and showed the potential for combined anti-cancer therapy through long-term immune activation mediated by PD-L1/PD-1 checkpoint blockade and anti-metastasis mediated by VEGFR2 blockade.

Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.

Fat grafting is widely utilized in reconstructive and esthetic plastic surgery, typically with minimal complications. Nevertheless, the occurrence of fat necrosis is dependent on the technique used for fat extraction, tissue processing and the volume of the graft. The longevity of the graft critically depends on the presence of adipose-derived stromal cells (ADSC) and their promotion of a reconstituted vascular supply.

This study seeks to determine whether there are differences in 13 angiogenesis-related adipokines based on their grouping by vascular endothelial growth factor (VEGF) expression levels.

The expression of 14 adipokines related to angiogenesis in 12 cultured ADSCs was evaluated using Human Adipokine Profiler kits, which simultaneously detect 58 mediators. Adipokines of the high and low VEGF expression groups were evaluated for their expression of the remaining 13 angiogenic proteins.

We were able to show that there are significant differences in VEGFlow and VEGFhigh ADSCs regarding fibroblast growth factor 19 (p = 0.043) and insulin like growth factor binding protein 3 (p = 0.028). Furthermore, ADSCs with differentially highly expressed VEGF show a different pattern in the amount of protein levels regarding the 13 other adipokines observed.

The VEGF has been described as a key angiogenic factor in fat grafts that may be linked to successful grafting; however, two of the fat samples analyzed exhibited high expression of VEGF but lacked significant co-expression of a range of other angiogenic factors. Thus, the assessment of the expression of predisposing mediators for graft angiogenesis for wound healing or contouring should include further angiogenesis promoters aside VEGF as parameters.

Bronchopleural fistula (BPF) is a serious complication that can occur after lung resection. This pilot study aimed to evaluate the effectiveness of autologous multilayered fibroblast sheet transplantation in reinforcing bronchial stump healing after lung resection in a canine model.

Four beagles underwent left caudal lobe excision. Two dogs received autologous multilayered fibroblast sheet transplantation on the stapled bronchial stump, while two served as controls. Fibroblast sheets generated from autologous oral mucosal fibroblasts were optimized for growth factor secretion. Fourteen days after lobectomy, the bronchial stumps were histologically and immunohistochemically analyzed to assess connective tissue formation, blood vessel formation, and inflammation.

Fibroblast sheets secreted high levels of pro-healing and pro-angiogenic factors in vitro. No adverse events or serious postoperative complications associated with the fibroblast sheet transplantation were observed. The cell sheet-transplanted group exhibited a layered structure of newly formed tissue around the bronchial stump. This was associated with enhanced blood vessel formation, as indicated by increased CD31-positive cells and high VEGF levels. The untreated control group showed a localized nodule of inflammation near the bronchial stump, which lacked evidence of blood vessel formation.

Autologous multilayered fibroblast sheet transplantation promoted connective tissue formation and blood vessel growth around the bronchial stump after lobectomy in a canine model. These findings suggest that fibroblast sheet transplantation is a promising therapeutic approach for preventing BPF after lung resection.

The natural, highly lipophilic bicyclic sesquiterpenes, Beta-Caryophyllene (BCP), was highlighted in several recent preclinical studies to enhance chemo-sensitization in chemo-resistant tumors and to efficiently inhibit angiogenesis and cancer cells' ability to invade and metastasize. Previous studies have researched the reasons for the synergistic effect of Beta-Caryophyllene in combination therapy and its role as a chemosensitizer and an inhibitor of angiogenesis through investigating the involved mechanisms and signaling molecules. These include the lipophilic nature of BCP, the selective interaction of BCP with CB2, the binding affinity of BCP to the receptor binding sites at the angiogenic vascular endothelial growth factor, and the upstream effect on JAK1/STAT3 pathway and other signaling pathways. Herein, the BCP role in enhancing chemo-sensitization of chemo-resistant tumors and in inhibiting angiogenesis and cancer cells' ability to invade and metastasize are highlighted. Beta-Caryophyllene appears to be a promising candidate in treating cancer when co-supplemented with drugs such as cisplatin, gemcitabine and sorafenib. Clinical trials are needed to validate the potential therapeutic effect of BCP as a co-supplementary drug in cancer therapy, helping to sensitize cancer response to drugs, modulating signaling pathways, and lowering the drugs' doses besides working as anti-angiogenetic drug.

Distant metastasis is one of the main reasons for treatment failure in nasopharyngeal carcinoma (NPC) patients. Tumour angiogenesis is a key basis for the distant metastasis of NPC. However, the molecular mechanisms underlying the mutual interaction between endothelial and NPC cells in tumour angiogenesis and NPC metastasis are still unclear. Here, we found that extracellular vesicles (EVs) mediate intercellular communication between endothelial cells and NPC cells, thereby promoting NPC cell migration, invasion, colony formation, and angiogenesis. Further experiments indicated that EV-mediated information exchange between endothelial cells and NPC cells upregulated the expression of the vascular endothelial growth factor receptor FLT1 in both types of cells. Mechanistically, FLT1-enriched EVs promoted NPC metastasis through the PI3K/AKT pathway and increased tumour angiogenesis, tumour growth, and distant lung and liver metastasis of NPC in xenografted mice. This effect was achieved through the delivery and upregulation of FLT1 in both endothelial and NPC cells. Thus, our findings reveal that FLT1-enriched EVs induce a positive feedback loop between NPC cells and endothelial cells to promote tumour angiogenesis and tumour metastasis. These results increase our understanding of the intricate interplay between tumour angiogenesis and distant metastasis and have major implications for the diagnosis and management of NPC patients with increased levels of FLT1-enriched EVs.

Epidemiological studies suggest a link between maternal exposure to PM2.5 during pregnancy and a higher incidence of fetal cardiovascular abnormalities. However, experimental data on the underlying mechanisms remain scarce.

This study aims to explore the effects of maternal PM2.5 exposure during pregnancy on fetal cardiovascular maldevelopment in a rat model.

Twenty-eight pregnant rats were divided into control and PM2.5-exposed groups according the exposure doses (N = 7 per group). Rats were administered with PM2.5 suspensions corresponding to 0, 2.6, 5.5, and 11 μg/d, respectively, during gestation. On gestational day 21, neonatal hearts were collected, and levels of cardiac transcription factors (Tbx2, Tbx20, Hand2 and Gata6), MMP9, TN-C, VEGF-A, NF-κB, apoptotic markers (Bax/Bcl-2 ratio), catalase (CAT), and lipid metabolism indicators were measured.

In the 11 μg/d group, the mRNA levels of Tbx2, Tbx20, Hand2, Gata6, MMP9, TN-C and VEGF-A, the protein levels of Tbx2, Hand2, and TN-C, and blood CAT activity were significantly reduced (P < 0.05). Conversely, NF-κB, Bax/Bcl-2, and serum markers of dyslipidemia (TC, TG, LDH, LDL-C/HDL-C) were significantly elevated (P < 0.05). Additionally, TN-C and Hand2 mRNA levels were reduced in the 2.6 μg/d group, and LDH level was increased in the 5.5 μg/d group (P < 0.05).

Maternal PM2.5 exposure during pregnancy is associated with fetal cardiovascular maldevelopments, possibly through the changes of cardiac transcription factors, vascular dysfunction, oxidative stress, apoptosis, and abnormalities of lipid metabolism.

The translation of biomedical devices and drug research is an expensive and long process with a low probability of receiving FDA approval. Developing physiologically relevant in vitro models with human cells offers a solution to not only improving the odds of FDA approval but also to expand our ability to study complex in vivo systems in a simpler fashion. Animal models remain the standard for pre-clinical testing; however, the data from animal models is an unreliable extrapolation when anticipating a human response in clinical trials, thus contributing to the low rates of translation. In this review, we focus on in vitro vascular or angiogenic models because of the incremental role that the vascular system plays in the translation of biomedical research. The first section of this review discusses the most common angiogenic cytokines that are used in vitro to initiate angiogenesis, followed by angiogenic inhibitors where both initiators and inhibitors work to maintain vascular homeostasis. Next, we evaluate previously published in vitro models, where we evaluate capturing the physical environment for biomimetic in vitro modeling. These topics provide a foundation of parameters that must be considered to improve and achieve vascular biomimicry. Finally, we summarize these topics to suggest a path forward with the goal of engineering human in vitro models that emulate the in vivo environment and provide a platform for biomedical device and drug screening that produces data to support clinical translation.

Alveolar echinococcosis (AE), a lethal parasitic zoonosis mimicking malignant tumors, progresses via hepatic infiltration and metastatic spread, causing multiorgan failure. Despite its clinical resemblance to cancer, molecular drivers of its aggressiveness remain poorly defined. Recent studies highlight perilesional angiogenesis as pivotal for lesion invasiveness, mediated by VEGF-driven pathological vascularization. VEGF not only fuels parasitic proliferation by creating nutrient-rich microenvironments but also engages crosstalk with host-parasite interactions, including immune evasion by Echinococcus multilocularis, germinal layer hyperplasia, and periparasitic inflammation.Targeting the HIF-1α/VEGF/VEGFR2 axis emerges as a promising therapeutic strategy. Mechanistically, VEGF/VEGFR2 blockade may simultaneously disrupt angiogenesis-dependent parasitic expansion and survival pathways. Preclinical evidence shows that inhibiting HIF-1α (VEGF's upstream regulator) suppresses metacestode proliferation and tissue invasion by starving lesions of vascular support while modulating immune-inflammatory responses. This dual action addresses both parasitic resource acquisition and host defence subversion.This review synthesizes molecular insights into HIF-1α/VEGF-mediated pathogenesis with clinical observations, proposing anti-angiogenic therapy as a rational adjunct to current treatments. By delineating VEGF's role in sustaining parasitic metabolic demands and immune regulation, we underscore the translational potential of pathway-specific inhibitors. Such approaches could mitigate limitations of conventional therapies (e.g., benzimidazoles), particularly for advanced-stage AE with microvascular proliferation. Systematic analysis of angiogenesis signalling networks advances our understanding of AE's "parasitic cancer" paradigm while guiding development of targeted interventions to improve patient outcomes.

The development of magnesium-based intraocular drug delivery devices holds significant promise for biomedical applications, particularly in treating wet age-related macular degeneration (AMD) using vascular endothelial growth factor inhibitors such as bevacizumab. Magnesium's rapid degradation, which can be finely tuned to achieve the controlled release required for AMD treatment, along with its well-established biocompatibility and biodegradable properties, positioning it as an ideal material for these applications. The study aimed to evaluate magnesium's potential as a carrier for ocular drug delivery systems by demontrating the stability of monoclonal antibodies, specifically bevacizumab, in the presence of magnesium corrosion products and the biocompatibility of these products with various cell lines, including murine fibroblasts (3T3), rat retinal Müller cells, and human retinal pigment epithelial cells (ARPE19). The stability of bevacizumab with pure magnesium (Mg) was investigated through an indirect enzyme-linked immunosorbent assay protocol, developed and customized for this specific aim. The biocompatibility of Mg corrosion products was assessed by toxicological evaluations through MTT and Trypan Blue Viability assays, along with cell cycle analysis. Results demonstrated no significant impact of Mg corrosion products on bevacizumab stability, with changes in mean values consistently below or equal to 10%. Furthermore, Mg extracts showed minimal cytotoxicity, as metabolic activity exceeded 80% across all cell lines, classified as Grade 0/1 cytotoxicity under ISO 10993-5 standards. Cell viability, proliferation, and morphology remained unaffected for up to 72 h of exposure. This study provides the firstin vitroevaluation of bevacizumab's stability in the presence of magnesium corrosion products and its biocompatibility with retinal cell lines, laying the foundation for future ophthalmic research and underscoring magnesium's potential as a material for intraocular drug delivery systems.

Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS-MAPK, PI3K-AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody-drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.

Tyrosine kinase inhibitors (TKIs) can treat various cancers, primarily through their antiangiogenic effects. However, as angiogenesis is crucial for successful wound healing, TKIs may adversely impact wound repair. This review analysed all 63 FDA-approved TKIs and identified evidence for wound healing and repair implications in 24 agents. The primary mechanism contributing to impaired wound healing appears to be the inhibition of vascular endothelial growth factor receptors, with secondary targets, such as epidermal growth factor receptors and platelet-derived growth factor receptors, potentially playing a role. Information from safety package inserts, preclinical studies, case reports and clinical trials suggests that these TKIs can cause delayed or impaired wound healing. The safety information generally recommends discontinuing treatment for at least one to 2 weeks before elective surgery and resuming treatment only after adequate wound healing has occurred. Neoadjuvant therapy with TKIs may be feasible if sufficient time is allowed between the cessation of the TKI and the onset of surgery. As the use of TKIs continues to increase, healthcare professionals should be aware of their potential impact on wound healing and take appropriate precautions to minimise the risk of wound-related complications.

In the era of precision oncology, systemic therapies for colon cancer are becoming increasingly biomarker-led, with implications for patients in the neoadjuvant, adjuvant and metastatic settings. As the landscape for colon cancer treatment evolves and becomes more complex, it is important that all members of the multidisciplinary team keep abreast of developments to ensure the most effective care is delivered to patients. As core members of the colorectal multidisciplinary team, Radiologists play a central role throughout the patient journey. This review serves as an educational summary of current and emerging treatment pathways in colon cancer, standards for biomarker testing, mechanisms of action for key drugs, important treatment-related complications, relevant tumour biology that underpins patterns of disease and treatment response, and the specific implications systemic therapies have for cancer imaging and Radiologists. We also highlight the increasing role for radiology in patient stratification and the importance of imaging biomarkers. It is crucial that Radiologists understand the current landscape of colon cancer treatment and emerging strategies on the horizon in clinical trials. Only through engagement across the wider multidisciplinary team will we deliver true personalised medicine for patients with colon cancer.

Chronic subdural hematoma (cSDH) presents a multifaceted challenge in contemporary neurological practice, necessitating innovative therapeutic strategies. This comprehensive review explores the convergence of two promising interventions: statins and middle meningeal artery (MMA) Embolization. With cSDH incidence on the rise, particularly among the aging population and those with long-term anticoagulant usage, the traditional surgical avenues face limitations in recurrence rates and associated risk factors. Statins, heralded for their anti-inflammatory, vasculogenic, and angiogenic properties, are emerging as potential allies in cSDH management. Concurrently, MMA embolization offers a nuanced approach to target the neomembrane's blood supply, with evidence supporting its efficacy and safety. However, the synthesis of MMA embolization with statins remains relatively unexplored, presenting a complex interplay between inflammation modulation and blood supply interruption.

The association between rheumatoid arthritis (RA) risk and specific variants of the Vascular Endothelial Growth Factor A (VEGFA) gene remains contentious. This study sought to elucidate the correlations between RA risk and several VEGFA gene variants, including VEGFA-634 (rs2010963), VEGFA-C936 (rs3025039), VEGFA-2578 (rs699947), VEGFA-1154 (rs1570360), through a comprehensive meta-analysis. We systematically reviewed literature from the Cochrane Library database, Embase, PubMed, Web of Science, China National Knowledge Infrastructure, and the Wanfang Data Information Service platform to gather relevant case-control studies. Using odds ratio (OR) and 95% confidence interval (95% CI), we analyzed the data to assess potential correlations. Sensitivity analysis and the Egger's test were employed to ensure the results stability and to evaluate potential publication bias. Additionally, trial sequential analysis (TSA) was conducted to validate the findings. Our meta-analysis incorporated ten studies involving 2817 patients and 2855 controls. Results indicated that the AA genotype of VEGFA-1154 (rs1570360) is associated with a reduced risk of RA in the overall population (AG + GG vs AA: P = 0.032 OR = 1.932 95% CI 1.059-3.523). However, no significant association is found for VEGFA-634 (rs2010963), VEGFA-C936 (rs3025039), and VEGFA-2578 (rs699947) variants with RA risk. Subgroup analysis revealed a significant association between the VEGF rs3025039(C936) variant and RA risk in the PCR-RFLP group under the TC vs. CC model. TSA confirmed the sufficiency of the sample size for robust conclusions. These findings suggest that the G allele of VEGFA-1154 (rs1570360) may increase RA risk, whereas the A allele appears to confer a protective effect. This study enhances our understanding of the genetic predispositions to RA and underscores the potential role of VEGFA gene variants in its pathogenesis.

Recent studies have suggested that sVEGFR3 is involved in cardiac diseases by regulating lymphangiogenesis; however, results are inconsistent. The aim of this study was to investigate the function and mechanism of sVEGFR3 in myocardial ischemia/reperfusion injury (MI/RI). sVEGFR3 effects were evaluated in vivo in mice subjected to MI/RI, and in vitro using HL-1 cells exposed to oxygen-glucose deprivation/reperfusion. Echocardiography, TTC-Evans blue staining, ELISA, electron microscopy, immunofluorescence, western blotting, and flow cytometry were used to investigate whether sVEGFR3 attenuates I/R injury. Transcriptome sequencing was used to investigate the downstream mechanism of sVEGFR3. Results showed that, in vivo, sVEGFR3 pretreatment reduced cardiac dysfunction, infarct area, and myocardial injury indicators by reducing ROS production, AIF expression, and apoptosis. In vitro, sVEGFR3 restored mitochondrial homeostasis by stabilizing the mitochondrial membrane potential (MMP) and preventing the opening of mitochondrial permeability transition pores (mPTP). And sVEGFR3 inhibits mitochondrial apoptosis through the Ras/MEK/ERK pathway. Furthermore, I/R injury increased the proportion of M1 macrophages and CD4 + T cells in myocardial tissue, as well as serum IFN-γ and TNF-α levels, whereas sVEGFR3 treatment attenuated these effects. sVEGFR3 attenuates MI/RI by regulating mitochondrial homeostasis and immune cell infiltration, and reduces intrinsic ROS-mediated mitochondrial apoptosis via the Ras/MEK/ERK pathway.

Premature ovarian failure (POF) is a disease that seriously jeopardizes women's physical and mental health worldwide. Zisheng Tongmai decoction (ZSTMD), a famous Traditional Chinese Medicine (TCM) formula, has a marked effect on the clinical treatment of POF. This study investigated the potential mechanism of ZSTMD to improve POF through network pharmacology and experimental validation. The active components, key targets and potential mechanisms of ZSTMD against POF were predicted by network pharmacology and molecular docking. The POF model was induced in rats by cyclophosphamide (CTX) and subsequently gavaged with different doses of ZSTMD. KGN cells were treated with different concentrations of quercetin and CTX. Histopathological were observed via hematoxylin and eosin (H&E) staining and immunofluorescence staining. Serum estrogen levels were detected via ELISA. Protein expression was detected via Western blot. We identified quercetin as the main active ingredients targeting VEGFA. Molecular docking showed that VEGFA interacted well with the main active components of ZSTMD. In vivo experiments, ZSTMD significantly increased body weight and the ovarian index, significantly increased E2 and AMH, and decreased FSH and LH in POF rats. Histologic results showed that ZSTMD increased the number of follicles and vascular density in the ovary. It also increased VEGFA and CD31 protein expression. In vitro experiments, quercetin suppressed CTX-induced apoptosis in KGN cells and increased VEGFA protein expression. Our study demonstrated that ZSTMD improves POF by promoting angiogenesis through VEGFA target.

Exosomes, as mediators of intercellular communication, can be released from different types of cells and regulate the function of the target cell by transferring cargo, such as proteins, DNA, and RNA. Recent investigations have revealed a preponderance of long noncoding RNAs (lncRNAs), a subclass of noncoding RNAs, within exosomes, where they exhibit notable stability and are implicated in the development and progression of neoplastic processes, such as tumor angiogenesis. Angiogenesis, as a hallmark of cancer, provides diffusible nutrients and oxygen to the distant cells and guarantees tumorigenesis and metastasis. Exosomal lncRNAs, including MALAT1, OIP5-AS1, PART1, SNHG family, FAM225A, ATB, RAMP2-AS1, UCA1, TRPM2-AS, FGD5-AS1, and LINC0016, could modulate tumor angiogenesis by activating signaling cascades and mediators within the target cells, such as microRNAs (miRNAs). Regulation of tumor angiogenesis through modulation of exosomal lncRNAs could be a reliable strategy for cancer therapy. In this review, we discuss the characteristics and biogenesis of exosomes and lncRNAs and how exosomal lncRNAs are involved in various processes of tumorigenesis. Our primary focus is on exosomal lncRNAs, their impact on tumor angiogenesis, and their potential as novel diagnostic markers and therapeutic targets for various cancers.

Many rhodopsin-like G-protein-coupled receptors (Rh-GPCRs) are known to either promote or inhibit angiogenesis. Among these, Opsin 4 and Opsin 5 are specifically involved in vascular development within the eye. Opsin 3 (OPN3), another member of Rh-GPCRs, performs a variety of light-dependent and light-independent functions in extraocular tissue. However, its role in endothelial cells and angiogenesis remains unclear. Here, we found that OPN3 knockdown or knockout in zebrafish impairs embryonic angiogenesis and vascular development. Similarly, silencing OPN3 in human umbilical vein endothelial cells (HUVECs) inhibits cellular proliferation, migration, sprouting, and tube formation, while OPN3 overexpression promotes these cellular processes. Moreover, OPN3 regulates angiogenesis in HUVECs through the VEGFR2-AKT pathway, with OPN3 and VEGFR2 co-localizing at the plasma membrane and forming a physical complex. These findings provide new insights into the non-light-dependent functions of OPN3 in angiogenesis, expanding our understanding of its physiological roles and offering potential therapeutic strategies for angiogenesis-related diseases.

Background/Objectives: Worldwide, colon cancer is a major cause of cancer-related mortality, with an increasing incidence influenced by genetic, environmental, and lifestyle factors. Despite advances in diagnosis and personalized treatments, challenges remain in improving patient prognosis, particularly in metastatic colorectal cancer (mCRC). Bevacizumab (BEV), a monoclonal antibody, is widely used in colorectal cancer treatment. This study aimed to analyze adverse events associated with BEV compared with other therapies based on data from the EudraVigilance (EV) database. Methods: A descriptive and disproportionality analysis was conducted on signals reported in the EV database related to BEV. The study included comparisons with other antineoplastic treatments, such as chemotherapy, targeted therapy, and immunotherapy. Patient demographics, severity of adverse drug reactions (ADRs), and distribution patterns were analyzed to assess the safety profile of BEV in colorectal cancer treatment. Results: The majority of the signals for BEV were from patients aged 18-64 years (39.42%) and 65-85 years (34.08%). Hypertension, thromboembolism, proteinuria, and gastrointestinal disorders have been the most frequently reported. Serious ADRs, including gastrointestinal perforations, hemorrhage, and arterial thromboembolism, were observed in 93.74% of Individual Case Safety Reports. BEV was associated with a higher likelihood of vascular and endocrine disorders compared with chemotherapy and other targeted therapies. Immunotherapy was linked to increased immunological ADRs, while BEV demonstrated fewer immune-related toxicities. Conclusions: Continuous monitoring is necessary to optimize patient management, particularly in elderly patients or those with cardiovascular comorbidities. Understanding BEV's safety profile allows for better personalization of treatment strategies, minimizing risks while enhancing therapeutic outcomes.

The "angiogenesis switch"-defined as the active process by which solid tumors develop their own circulation-plays an important role in both tumoral growth and propagation. As the malignant tumor grows and reaches a critical size, the metabolic needs as a function of an ever-increasing distance to the nearest emergent blood vessel, can no longer be covered by the microenvironment of the peritumoral tissue. Although a relatively discrete process, the "angiogenic switch" acts as a limiting stage of tumoral development present from the avascular hyperplasia phase to the vascularized neoplastic phase, providing support for tumor expansion and metastasis. Over time, research has focused on blocking the angiogenetic pathways (such as VEGF/VEGFR signaling axis) leading to the development of targeted therapeutic agents such as Bevacizumab. Objectives: We conducted a review of the molecular principles of tumoral angiogenesis and we tried to follow the history of Bevacizumab from its first approval for human usage 20 years ago to current days, focusing on the impact this agent had in solid tumor therapy. A comprehensive review of clinical trials pertaining to Bevacizumab (from the era of the preclinic trials leading to approval for human usage, to the more recent randomized trial focusing on combination targeted therapy) further details the role of this drug. We aimed to establish if this ancient drug continues to have a place in modern oncology. Conclusions: Bevacizumab, one of the first drugs targeting tumoral microenvironment, remains one of the most important oncologic agents blocking the VEGF/VEGFR angiogenic pathway. otherwise, history of 20 years marked by numerous controversies (ranging from methodological errors of clinical trials to withdrawal of approval for human usage in breast cancer patients, from discussions about severe side effects to resistance to therapy and limited efficacity), Bevacizumab continues to provide an optimal therapeutic option for many solid tumors that previously had little to no means of treatment, improving otherwise bleak outcomes. Even in the era of personalized precision oncology, Bevacizumab continues to be a key element in many therapeutic regimens both as monotherapy and in combination with newer targeted agents.

Inflammation is an essential component of the immune response that protects the host against pathogens and facilitates tissue repair. Chronic inflammation is a critical factor in cancer development and progression. It affects every stage of tumor development, from initiation and promotion to invasion and metastasis. Tumors often create an inflammatory microenvironment that induces angiogenesis, immune suppression, and malignant growth. Immune cells within the tumor microenvironment interact actively with cancer cells, which drives progression through complex molecular mechanisms. Chronic inflammation is triggered by factors such as infections, obesity, and environmental toxins and is strongly linked to increased cancer risk. However, acute inflammatory responses can sometimes boost antitumor immunity; thus, inflammation presents both challenges and opportunities for therapeutic intervention. This review examines how inflammation contributes to tumor biology, emphasizing its dual role as a critical factor in tumorigenesis and as a potential therapeutic target.

The development of novel therapeutics in neuro-oncology faces significant challenges, often marked by high costs and low success rates. Despite advances in molecular biology and genomics, targeted therapies have had limited impact on improving patient outcomes in brain tumors, particularly gliomas, due to the complex, multigenic nature of these malignancies. While significant efforts have been made to design drugs that target specific signaling pathways and genetic mutations, the clinical success of these rational approaches remains sparse. This review critically examines the landscape of neuro-oncology drug discovery, highlighting instances where serendipity has led to significant breakthroughs, such as the unexpected efficacy of repurposed drugs and off-target effects that proved beneficial. By exploring historical and contemporary cases, we underscore the role of chance in the discovery of impactful therapies, arguing that embracing serendipity alongside rational drug design may enhance future success in neuro-oncology drug development.

Anti-vascular endothelial growth factor (VEGF) agents in combination with immunotherapies have improved outcomes for cancer patients, but predictive biomarkers have not been elucidated. We report here a preplanned analysis in the previously reported APPLE study, a phase 3 trial evaluating the efficacy of the bevacizumab in combination with atezolizumab, plus platinum chemotherapy in metastatic, nonsquamous non-small cell lung cancer (NSCLC). We investigated the correlation of serum VEGF-A and its isoforms at baseline with treatment response by using an enzyme-linked immunosorbent assay. We reveal that the addition of bevacizumab significantly improves the progression-free survival in patients with the low VEGF-A level. Our results demonstrate that measuring serum VEGF-A or its isoforms may identify NSCLC patients who are likely to benefit from the addition of bevacizumab to immunotherapy. These assays are easy to measure and have significant potential for further clinical development.